Process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate

ABSTRACT

The present invention relates to a process for the preparation of 4-aminomethyl-3-alkoxyiminopyrrolidine methane-sulfonate, a key intermediate of quinolone antibiotics. According to the process of the present invention, the total number of steps has been shortened to 2-3 steps, the solid separation is not required, and the use of costly chemicals, particularly (BOC) 2 O (t-butoxycarbonyl anhydride), several organic solvents and reactants, is eliminated.

TECHNICAL FIELD

The present invention relates to a process for preparing4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate of the followingformula (I):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, which is a usefulintermediate for preparing quinolone antibiotics, particularly(R,S)-7-(3-aminomethyl-4-syn-alkoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid of the following formula (VI):

wherein R is as defined above, salt, or hydrate thereof as described inU.S. Pat. No. 5,633,262 and EP 0 688 772 A1.

The process of the present invention adopts a new synthetic pathwayhaving shortened number of steps for preparing Compound (I) comparedwith the earlier processes, whereby Compound (I) is produced in a highyield. Accordingly, the present invention cuts the production cost down,and ultimately contributes to economic preparation of Compound (VI).

Background Art

WO99/44991 and WO01/17961 disclose a process for preparing Compound (I)as depicted in Reaction Scheme 1:

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, and P and P₂ eachrepresent the same or different protecting group.

WO99/44991 specifically describes a process from Compound (II) toCompound (3) in the above Reaction Scheme 1, which consists of tworeduction steps of the nitrile group and one protection step of theamine group.

Compound (1) is produced from Compound (II) by a hydrogenation processusing such a catalyst as Ra—Ni, etc. for the first reduction of nitrilegroup. As the solvent, a mixture of water and isopropyl alcohol is usedin an amount of 2 to 20 equiv with respect to Compound (II).

Compound (2) is produced from Compound (1) by protecting the aminegroup. As the protecting group, formyl, acetyl, trifluoroacetyl,benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, benzyloxycarbonyl, p-methoxy-benzyl, trityl,tetrahydropyranyl, pivaloyl, etc. may be used. Among these protectinggroups, t-butoxycarbonyl is particularly preferred. However, (BOC)₂Oused for the introduction of the t-butoxycarbonyl group is an expensivereagent to contribute about ⅓ of the total cost for preparing Compound(2) from Compound (1). Furthermore, the reaction temperature isdifficult to control due to high exothermic and fast reaction rate.Failure of the control of the reaction temperature led to the formationof the dimer of Compound (2). Also, Compound (2) should be separatedthrough an extractive work-up and solidification process. These work-upprocesses make this process complicate.

Compound (3) is produced from Compound (2) by the second hydrogenationprocess using Pd/C catalyst. The catalyst is used in an amount of0.5-20% by weight, and an amine or buffer solution is used to preventreduction of the carbonyl group at 3-position of the pyrrolidine ring.

The process for preparing Compound (I) from Compound (4) is disclosed inWO01/17961, wherein the protecting group is removed usingmethanesulfonic acid to form a salt. However, this process requires tworecrystallization processes to produce high quality product. Theseoperations lowered the productivity and resulted in low yield.

Differently from the Reaction Scheme 1 above, EP 0 688 772 A1 describesa process for preparing Compound (4) from Compound (II) as depicted inReaction Scheme 2.

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, and P and P′ eachrepresent the same or different protecting group.

EP 0 688 772 A1 provides a process for preparing Compound (4) fromCompound (II) wherein the carbonyl and nitrile groups are reducedsimultaneously to give the amino alcohol intermediate, and the alcoholgroup is selectively oxidized to give the carbonyl group again. Thisprocess requires reagents difficult to be applied to the industrialproduction, and so has little merit compared with the process ofWO99/44991. Particularly, this process uses a homogeneous catalyst forthe hydrogenation of the nitrile group, but preparation of thehomogeneous catalyst and its recovery and reproduction after thereaction are not easy.

DISCLOSURE

As mentioned above, the earlier processes for preparing Compound (I)have such problems as complicated process, high production cost, poorreproducibility, etc., and so it has been required to develop animproved new process.

Extensive study led to the present invention wherein the two stephydrogenation of WO99/44991 is converted into one step hydrogenation,and the use of expensive organic reagents, particularly (BOC)₂O, andvarious organic solvents and reagents is avoided.

Therefore, the present invention provides a new and effective processfor preparing Compound (I).

The present invention also provides a process for preparing Compound(VI) by using Compound (I) prepared by the above process.

The present invention also provides new intermediates used in theprocess for preparing Compound (I).

BEST MODE FOR CARRYING OUT THE INVENTION

As the first aspect, the present invention provides a process forpreparing Compound (I):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, which comprises thesteps of,a) reacting Compound (II):

wherein P represents a protecting group, with alkoxyamine orhaloalkoxyamine or salt thereof in the presence of a base to giveCompound (III):

wherein R and P each are as defined above,b) reacting Compound (III) with methanesulfonic acid to give Compound(IV):

wherein R is as defined above, andc) adding methanesulfonic acid and hydrogenation catalyst to Compound(IV) and subjecting the compound to hydrogenation reaction to giveCompound (I).

In the above process, the protecting group P may include formyl, acetyl,trifluoroacetyl, benzoyl, p-toluenesulfonyl, methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl,trityl, tetrahydropyranyl, pivaloyl, etc., and the most preferable oneis t-butoxycarbonyl (BOC). Also, R is preferably methyl.

The above process for preparing Compound (I) may be depicted as follows:

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, and P represents aprotecting group.

Step (a)

The process for converting Compound (II) into Compound (III) is carriedout in the presence of a base. A preferably used base includestriethylamine, tri-n-butylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, 4-(4-methyl-piperidin-1-yl)-pyridine, andsodium acetate. The base is preferably used in an amount of 0.01˜10equiv with respect to Compound (II).

The reactant, alkoxyamine or haloalkoxyamine, is preferably used in theform of an acid addition salt, particularly hydrochloride form. Thealkoxyamine, haloalkoxyamine, or salt thereof is used in an amount of 1to 2 equiv with respect to Compound (II).

Solvents, which can be used in this step include water, organic solvent,or a mixture thereof, preferably straight-chain or branchedC₁₋₆-alcohol, more preferably MeOH, EtOH, or IPA (isopropyl alcohol).

The reaction temperature and time in step (a) may be varied depending onthe base and solvent used. The reaction temperature ranges, for example,from room temperature to 200° C. But, a person skilled in the art mayeasily determine the appropriate reaction temperature and time accordingto the base and solvent used.

One best mode of the present invention is to use triethylamine as thebase. In this case, Compound (II) is refluxed with alkoxyaminehydrochloride in the presence of triethylamine and methanol for 22hours.

Another best mode of the present invention is to use sodium acetate asthe base. In this case, Compound (II) is added to a solution ofalkoxyamine hydrochloride and sodium acetate in ethanol or methanol, andthe mixture is refluxed for about 18 hours.

Another best mode of the present invention is to use pyridine as thebase. In this case, Compound (II) is added to a solution of alkoxyaminehydrochloride and pyridine in isopropyl alcohol or methanol, and themixture is reacted with stirring for about 5 hours. This process isconvenient because it is carried out at room temperature.

The pure Compound (III) may be obtained by applying the processesexemplified in the above best modes without any side product that isdetected by HPLC.

Step (b)

The reaction from Compound (III) to Compound (IV) is to remove theprotecting group by methanesulfonic acid. Methanesulfonic acid is usedin an amount of about 0.5 to 3 equiv, preferably about 1 to 1.2 equivwith respect to Compound (III). The protecting group is easily removedby such an acid as methanesulfonic acid. As shown in the examples below,it can be identified by NMR, HPLC, etc. that the protecting group iseasily removed by about 30 minutes' reflux.

Step (c)

The reaction from Compound (IV) to the desired compound, Compound (I),is a selective hydrogenation reaction using such Raney type metalcatalysts as Raney-Ni, Raney-Co, etc. or metal catalysts incorporatedinto supports such as activated carbon, alumina, silica, etc. Metalsused as the active site of the catalyst include the metals like Ni, Co,Pt, Pd, Ru, Rh, Ir, Cu, etc. and the palladium precursors like palladiumchloride, palladium nitrate, palladium acetate, etc., but the palladiumcatalyst is more preferable. Usually, activity of the catalyst may bechanged by the influence of other metals added in a small amount in theform of a co-catalyst, or by reaction conditions such as pressure,temperature, etc., and so the selectivity for the desired product can becontrolled thereby. The hydrogenation catalyst particularly preferablefor being used in the present invention is Pd catalyst not only having 1to 20% by weight of Pd but also incorporated in a support selected fromthe group consisting of carbon, silica, and alumina. This hydrogenationcatalyst is preferably used in an amount of 0.01 to 10% by weight withrespect to Compound (IV) based on the metal component.

The hydrogenation reaction is carried out preferably under thetemperature range of 0 to 50° C. and the hydrogen pressure of 1 to 100atm.

Methanesulfonic acid is added to the reaction solution in an amount ofabout 0.5 to 3 equiv, preferably about 1 to 1.2 equiv with respect toCompound (III).

As the solvent used in this step, one or more organic solvents selectedfrom the group consisting of methanol, ethanol, n-propanol, isopropanol,tetrahydrofuran, dimethoxyethane, dioxane, ethyl acetate anddichloromethane, preferably methanol can be mentioned.

The step (c) reaction may also be carried out in the presence of an acidas a further additive. The acid includes hydrochloric acid, nitric acid,sulfuric acid, acetic acid, methanesulfonic acid, etc., andmethanesulfonic acid is the most preferable. In order to increase theyield, it is preferable to add the acid in an amount to control thereaction solution to pH 1 to 2.5 during the hydrogenation reaction, andthe acid may be added to the reaction solution at the time ofinitiation, or continuously in the middle, of the reaction.

As the second aspect, the present invention provides a process forpreparing Compound (I):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, which comprises thesteps of,a) reacting Compound (II):

wherein P represents a protecting group, with alkoxyamine orhaloalkoxyamine or salt thereof in the presence of a base to giveCompound (III):

wherein R and P each are as defined above, andb) adding methanesulfonic acid and hydrogenation catalyst to Compound(III) and subjecting the compound to hydrogenation reaction to giveCompound (I).

In the above process, R is preferably methyl and P is preferablyt-butoxycarbonyl (BOC).

The above process for preparing Compound (I) may be depicted as follows:

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, and P represents aprotecting group.

This second process has such merits as explained for the first process,and is more effective since the number of steps is decreased from 3 to2.

Step (a)

Step (a) of the second process is carried out according to the samemanner as Step (a) of the first process.

Step (b)

In Step (b) of the second process, Steps (b) and (c) of the firstprocess are concurrently carried out.

The amount of methanesulfonic acid is the total amount ofmethanesulfonic acid used in Steps (b) and (c) of the first process,i.e., about 1 to 6 equiv, preferably about 1.5 to 2.5 equiv with respectto Compound (III). Further, the hydrogenation catalyst is introduced inan amount of 0.01 to 10% by weight with respect to Compound (III) basedon the metal component.

The solvent used in Step (b) of the second process is an organic solventselected from the group consisting of methanol, ethanol, n-propanol,isopropanol, tetrahydrofuran, dimethoxyethane, dioxane, ethyl acetateand dichloromethane, or a mixture of this organic solvent and water. Themixture of an organic solvent and water is more preferable. When themixture is used, the mixing ratio is between 0.2 to 50 volumes of theorganic solvent to 1 volume of water. Particularly preferable solvent isa mixture of methanol and water.

Besides, the same reaction conditions as Step (c) of the first processmay be applied to this step.

As the third aspect, the present invention provides a process forpreparing Compound (VI):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, salt or hydratethereof, which comprises the step of reacting Compound (I):

wherein R is as defined above, which is prepared according to the firstor second process as explained above, with Compound (V):

wherein X represents a leaving group, preferably halogen.

In this process, the reaction of Compound (I) with Compound (V) ispreferably carried out in the presence of a base and in a solvent. Thespecific reaction conditions may be easily controlled by a personskilled in the art by referring to PCT/GB00/03358.

Compound (VI) is preferably(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate or its hydrate.

As the fourth aspect, the present invention provides new Compound (III)with the following formula:

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, and P represents aprotecting group.

P is preferably t-butoxycarbonyl (BOC).

As the fifth aspect, the present invention also provides new Compound(IV) with the following formula:

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl.

Compounds (III) and (IV) above are useful as intermediates for preparingCompound (I).

The present invention will be more specifically explained by thefollowing examples. However, it should be understood that they do notintend to limit the present invention in any manner.

EXAMPLE 1

(1) Synthesis of Compound (III)

To a stirred solution of Compound (II) (10.5 g, 0.05 mol) in 100 ml ofmethanol in the presence of pyridine (4.84 ml, 1.2 equiv) was addedmethoxylamine hydrochloride (5.0 g, 1.2 equiv) at room temperature.After 5 hours, the completion of reaction was confirmed by HPLC underthe following conditions:

Column: Capcellpak C18

Solvent: AN/H₂O/TFA=60/40/0.1

Wavelength: 210 nm

Flow rate: 1 ml/min

Temperature: room temp.

The volatiles were thoroughly removed under vacuum, and ethyl acetate(50 ml) was added to the residue. The organic layer was washed twicewith saturated aqueous NaHCO₃ solution (100 ml) and twice with brine(100 ml). Anhydrous magnesium sulfate was added to the organic layer toremove the moisture, and the mixture was concentrated under vacuum togive Compound (III) (11.09 g, Yield 92.8%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.47(s, 9H), 3.69(dd, 1H), 3.95(s, 3H),3.98˜4.06(m, 2H), 4.10˜4.22(m, 2H)

(2) Synthesis of Compound (IV)

To a stirred solution of Compound (III) (3.0 g, 0.0125 mol) in 25 ml ofmethanol was added dropwise methanesulfonic acid (0.91 ml, 1.1 equiv,98%) and the mixture was heated at reflux for 30 minutes. The reactionmixture was cooled to room temperature. The mixture was concentratedunder reduced pressure and recrystallized to give Compound (IV) (4.14 g,Yield 98.8%).

¹H NMR (400 MHz, D₂O) δ (ppm): 2.69 (s, 3H), 3.76˜3.82 (dd, 1H), 3.88(s, 3H), 3.92˜3.98 (m, 2H), 4.03˜4.21 (dd, 2H)

(3) Synthesis of Compound (I)

To a stirred solution of Compound (IV) (4.19 g, 0.0125 mol) in 80 ml ofmethanol were added Pd/C (0.3 g, wet basis) as a catalyst andmethanesulfonic acid (1.0 ml, 1.1 equiv, 98%), and hydrogenationreaction was carried out for 24 hours under the reaction temperature of25° C. and hydrogen pressure of 500 psig. After the reaction wascompleted, the mixture was passed through a celite to remove thecatalyst, and the filtrate was concentrated under vacuum. Methanol (50ml) was added to the residue, and Compound (I) (1 mg) was added as aseed. The mixture was stirred at room temperature for 1 hour andfiltered. The resulting solid was dissolved in a water bath of about 50°C., recrystallized at −20° C., and filtered to give Compound (I) (0.99g, Yield 23.1%).

¹H NMR (400 MHz, DMSO) δ (ppm): 2.39 (s, 6H), 3.07 (dd, 1H), 3.16 (dd,1H), 3.24˜3.30 (m, 2H), 3.66˜3.73 (m, 1H), 3.87 (s, 3H), 3.97 (dd, 2H)

EXAMPLE 2

(1) Synthesis of Compound (III)

To a stirred suspension of Compound (II) (10.5 g, 0.05 mol) in 100 ml ofmethanol were added methoxylamine hydrochloride (5.0 g, 1.2 equiv) andtriethylamine (8.4 ml, 1.2 equiv) and the mixture was heated at refluxfor 22 hours. The reaction mixture was cooled to room temperature. Themixture was concentrated under vacuum, and ethyl acetate (50 ml) wasadded to the residue. The organic layer was washed twice with saturatedaqueous NaHCO₃ solution (100 ml) and twice with brine (100 ml).Anhydrous magnesium sulfate was added, filtered, and the filtrate wasconcentrated under vacuum to give Compound (III) (11.35 g, Yield 95.0%).

(2) Synthesis of Compound (IV)

Compound (IV) was prepared according to the same procedure as Example1(2).

(3) Synthesis of Compound (I)

Compound (I) was prepared according to the same procedure as Example1(3).

EXAMPLE 3

(1) Synthesis of Compound (III)

To a stirred suspension of Compound (II) (10.5 g, 0.05 mol) in 100 ml ofmethanol were added methoxylamine hydrochloride (5.0 g, 1.2 equiv) andsodium acetate (4.92 g, 1.2 equiv) and the mixture was heated at refluxfor 18 hours. The reaction mixture was cooled to room temperature. Themixture was concentrated under vacuum and ethyl acetate (50 ml) wasadded to the residue. The organic layer was washed twice with saturatedaqueous NaHCO₃ solution (100 ml) and twice with brine (100 ml).Anhydrous magnesium sulfate was added, filtered, and the filtrate wasconcentrated under vacuum to give Compound (III) (11.35 g, Yield 95.0%).

(2) Synthesis of Compound (IV)

Compound (IV) was prepared according to the same procedure as Example1(2).

(3) Synthesis of Compound (I)

Compound (I) was prepared according to the same procedure as Example1(3).

EXAMPLE 4

(1) Synthesis of Compound (III)

Compound (III) was prepared according to the same procedure as Example1(1).

(2) Synthesis of Compound (IV)

Compound (IV) was prepared according to the same procedure as Example1(2).

(3) Synthesis of Compound (I)

Compound (I) (0.72 g, Yield 16.8%) was prepared according to the sameprocedure as Example 1(3) except that the pressure in the hydrogenationreaction was lowered from 500 psig to 200 psig.

EXAMPLE 5

(1) Synthesis of Compound (III)

Compound (III) was prepared according to the same procedure as Example1(1).

(2) Synthesis of Compound (I)

To a 100 ml pressure reactor were added Compound (III) (5 g), methanol(40 ml) and water (10 ml). To this solution were added 10% Pd/C (0.18 g)and methanesulfonic acid (2.2 ml). The mixture was agitated at 30° C.under 100 psig of hydrogen for 1 hour. The catalyst was filtered out,and the filtrate was concentrated completely under reduced pressure. Theresidue was dissolved in methanol (10 ml) and Compound (I) (1 mg) wasadded as a seed at 5° C. to form crystal. The resulting crystal wascooled to −10° C. and filtered to give3-aminomethyl-4-Z-methyloxyiminopyrrolidine methanesulfonate (3.15 g,Yield 45%).

EXAMPLE 6

Synthesis of(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

Triethylamine (5.1 ml) was added to7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (3.05 g) in water (25 ml) at 15-20° C., and the mixture was stirredfor 20 minutes. Compound (I) (3.86 g) prepared in Example 1 and water (5ml) were added, and this mixture was stirred at 20-25° C. for 18 hours.The product thus obtained was filtered, and the filter cake was washedwith water (30 ml) and ethanol (30 ml). Drying at 50° C. under vacuumgave the title compound (4.23 g) as a white solid. The identificationdata were the same as those of the authentic sample.

EXAMPLE 7

Synthesis of(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methane-sulfonate

A solution of methanesulfonic acid (0.33 g, 3.43 mmol) indichloromethane (1 ml) was added to a suspension of(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid (1.5 g at a purity of 89.9%, 3.46 mmol) in a mixture ofdichloromethane (23.2 ml) and ethanol (2.7 ml) at 30° C. This mixturewas stirred at 30° C. for 3 hours, and then cooled to 20° C. andfiltered. The filter cake was washed with dichloromethane (20 ml) anddried at 50° C. under vacuum to give the title compound (1.71 g). Theidentification data were the same as those of the authentic sample.

EXAMPLE 8

Synthesis of(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate sesquihydrate

(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate (27.5 g at a purity of 91%, 51.4 mmol) was stirredin a mixture of isopropanol (150 ml) and water (75 ml) and then heatedto become a clear solution (52° C.). This solution was cooled to 34° C.,and(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate sesquihydrate was added thereto as a seed crystal.Thus obtained suspension was allowed to stand over 1 hour to 25° C. andthen stirred for 18 hours. The slurry was cooled to 0-4° C., stirred for2 hours, and filtered. The filter cake was washed with isopropanol (30ml). The product was dried by suction for 2 hours, and further driedunder vacuum at 50° C. The dried product was humidified by wet nitrogento give the title sesquihydrate (22.9 g, 92%). The identification datawere the same as those of the authentic sample.

Experiment 1

In order to determine whether Compound (I) prepared according to thepresent invention can be used as a material for antibiotics, Compound(I) prepared in Example 1 was analyzed by HPLC under the followingconditions:

Column: Shodex ODP-50 6E (4.6×250 mm, 5 μm, Asahipak)

Solvent: AN/H₂O (including 5 mM 1-hexanesulfonic acid)/TFA=5/95/0.1

Wavelength: 207 nm

Flow rate: 1 ml/min

Temperature: 40° C.

The contents of impurities and isomers were determined based on PAR(Peak Area Ratio) where the definition of PAR is as follows:PAR(%)=A/B×100wherein A means the peak area of each impurity, and B means the sum ofpeak areas of all the impurities except the peaks identified in theblank solution (consisting of solvent only, not the sample)

The quality standard for the impurities and isomers in terms of PAR bythe present applicant company, and the results of HPLC analysis thereonare represented in the followng Table 1.

TABLE 1 Analysis result for Compound (I) Quality Standard prepared inExample 1 E-isomer 2.7% PAR or less 0.96% PAR or less Specific 1.2% PARor less 0.88% PAR or less unconfirmed impurity New impurity 0.1% PAR orless 0.02% PAR or less

Further, Compounds (1), (2), (3), (4), etc. which are formed during theearlier processes for preparing Compound (I) were never detected.

All the Compounds (I) prepared according to Examples 2 to 5 alsosatisfied the quality standard.

INDUSTRIAL APPLICABILITY

In preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonateused as an intermediate for quinolone antibiotics, the present inventionimproved a couple of aspects of the previous process. Total number ofsteps is reduced to 2-3 steps to result in removing operations such asfiltration and extractive work-up, and use of expensive reagent,(BOC)₂O, various organic solvents and reagents is avoided.

1. A process for preparing Compound (I):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, which comprises thesteps of, a) reacting Compound (II):

 wherein P represents a protecting group, with alkoxyamine orhaloalkoxyamine or salt thereof in the presence of a base to giveCompound (III):

 wherein R and P each are as defined above, b) reacting Compound (III)with methanesulfonic acid to give Compound (IV):

 wherein R is as defined above, and c) adding methanesulfonic acid andhydrogenation catalyst to Compound (IV) and subjecting the compound tohydrogenation reaction to give Compound (I).
 2. The process of claim 1,wherein R is methyl.
 3. The process of claim 1, wherein P ist-butoxycarbonyl (BOC).
 4. The process of claim 1, wherein the base ofstep (a) is triethylamine, tri-n-butylamine, diisopropylethylamine,pyridine, 4-dimethylaminopyridine, 4-(4-methyl-piperidin-1-yl)-pyridine,or sodium acetate.
 5. The process of claim 1, wherein the base of step(a) is used in an amount of 0.01˜10 equiv with respect to Compound (II).6. The process of claim 1, wherein methanesulfonic acid is used in anamount of 0.5 to 3 equiv with respect to Compound (III) in steps (b) and(c).
 7. The process of claim 1, wherein the reaction of step (c) iscarried out in one or more solvents selected from the group consistingof methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran,dimethoxyethane, dioxane, ethyl acetate, and dichloromethane.
 8. Theprocess of claim 1, wherein the hydrogenation catalyst of step (c) is Pdcatalyst not only having 1 to 20% by weight of Pd but also incorporatedin a support selected from the group consisting of carbon, silica, andalumina.
 9. The process of claim 1, wherein the hydrogenation catalystof step (c) is used in an amount of 0.01 to 10% by weight with respectto Compound (IV) based on the metal component.
 10. The process of claim1, wherein the hydrogenation reaction of step (c) is carried out undertemperature range of 0 to 50° C. and hydrogen pressure of 1 to 100 atm.11. The process of claim 1, wherein alkoxyamine hydrochloride orhaloalkoxyamine hydrochloride is used.
 12. A process for preparingCompound (I):

wherein R represents C₁₋₄ alkyl or C₁₋₄ haloalkyl, which comprises thesteps of, a) reacting Compound (II):

 wherein P represents a protecting group, with alkoxyamine orhaloalkoxyamine of salt thereof in the presence of a base to giveCompound (III):

 wherein R and P each are as defined above, and b) addingmethanesulfonic acid and hydrogenation catalyst to Compound (III) andsubjecting the compound to hydrogenation reaction to give Compound (I).13. The process of claim 12, wherein R is methyl.
 14. The process ofclaim 12, wherein P is t-butoxycarbonyl (BOC).
 15. The process of claim12, wherein the base of step (a) is triethylamine, tri-n-butylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine,4-(4-methyl-piperidin-1-yl)-pyridine, or sodium acetate.
 16. The processof claim 12, wherein the base of step (a) is used in an amount of0.01˜10 equiv with respect to Compound (II).
 17. The process of claim12, wherein the reaction of step (b) is carried out in an organicsolvent selected from the group consisting of methanol, ethanol,n-propanol, isopropanol, tetrahydrofuran, dimethoxyethane, dioxane,ethyl acetate and dichloromethane, or in a mixture of this organicsolvent and water.
 18. The process of claim 17, wherein the reaction ofstep (b) is carried out in a mixture of the organic solvent and water.19. The process of claim 12, wherein methanesulfonic acid is used in anamount of 1 to 6 equiv with respect to Compound (III) in step (b). 20.The process of claim 12, wherein the hydrogenation catalyst of step (b)is Pd catalyst not only having 1 to 20% by weight of Pd but alsoincorporated in a support selected from the group consisting of carbon,silica, and alumina.
 21. The process of claim 12, wherein thehydrogenation catalyst of step (b) is used in an amount of 0.01 to 10%by weight with respect to Compound (III) based on the metal component.22. The process of claim 12, wherein the hydrogenation reaction of step(b) is carried out under temperature range of 0 to 50° C. and hydrogenpressure of 1 to 100 atm.
 23. The process of claim 12, whereinalkoxyamine hydrochloride or haloalkoxyamine hydrochloride is used.